Eslicarbazepine acetate is an anticonvulsant medication approved in Europe for adjunctive therapy in adults with partial-onset seizures. FDA approval is expected shortly for use in the United States. This article reviews the pharmacologic and pharmacokinetic profile of eslicarbazepine acetate, and factors that should be considered when using this medication.

Since 2009, eslicarbazepine acetate has been approved in Europe for adjunctive therapy in adults with partial-onset seizures.1 However, in May of 2010, the FDA declined to approve the drug for use in the United States based on the data provided at that time. In December of 2011, with data from a new clinical trial pending, Sunovion Pharmaceuticals (formerly Sepracor) announced their intentions to resubmit a new drug application to the FDA seeking approval for eslicarbazepine acetate as an adjunctive treatment of partial onset seizures in adults with epilepsy.2 FDA approval is expected in late 2012 or early 2013. Eslicarbazepine acetate will be released under the brand name Stedesa®.

Similar to carbamazepine and oxcarbazepine, the anticonvulsant activity of eslicarbazepine acetate is thought to come from blockade of fast-acting, voltage-gated sodium channels responsible for neuronal signal propagation.3 Eslicarbazepine acetate displays a greater affinity for the inactive state (already fired) of the sodium channel rather than the resting state (waiting to fire), meaning that it could be more selective for rapidly firing neurons.4 This is important for epilepsy patients because rapid or uncontrolled neuronal firing is thought to be responsible for propagation of seizures. Eslicarbazepine acetate may selectively target the area of the brain where the focal seizure occurs, causing fewer neurologic side effects overall.

Eslicarbazepine acetate is a pro-drug which is rapidly and extensively metabolized to eslicarbazepine (S- 10-monohydroxy-oxcarbazepine) through hydrolysis during first-pass metabolism. This is the major active metabolite of both eslicarbazepine acetate and oxcarbazepine. Minor metabolites (<5%) include R-licarbazepine and oxcarbazepine. Approximately one-third of the active and minor metabolites undergo glucuronidation and are eliminated by the kidneys.5,6 Up to 93% of the original dose can be recovered in the urine.7The elimination half-life is approximately 16 hours and steady state is reached in approximately 4 to 5 days.8 

Dosing recommendations and dosage forms have not been released, but in clinical trials the starting dose was 400 mg administered by mouth daily, which was then increased to a maintenance dose of 800 mg or 1200 mg by mouth daily.9,10,11 A phase II clinical trial showed that giving the total daily dose as a single dose achieved higher serum concentrations of the active metabolite and better seizure control overall when compared to dividing the dose twice daily.12 Dosage forms available in Europe include 200 mg, 400 mg, 600 mg, and 800 mg tablets.1 

Hepatic function

Dose adjustment based on hepatic function is probably not necessary in patients with mild to moderate liver failure. No data is available in patients with severe liver failure. The pharmacokinetics of eslicarbazepine acetate following an administration of 800 mg once daily for eight days was characterized in patients with moderate liver impairment (n=8) and normal liver function (n=8). There were no significant pharmacokinetic differences between hepatically impaired patients and control patients in concentrations of metabolites recovered in the urine.13 

Renal function

Dose adjustment may be necessary in patients with a creatinine clearance < 60 mL/min. Pharmacokinetic parameters following a single 800 mg dose were characterized in patients with normal renal function, mild renal impairment, moderate renal impairment, severe renal impairment, and end-stage renal disease requiring hemodialysis (n=8 for each group). The maximum concentration of eslicarbazepine did not differ between groups, but clearance was decreased and total exposure increased as renal function decreased. In patients with end-stage renal disease, hemodialysis was effective in removing eslicarbazepine metabolites from the bloodstream.7 

Age

Dose adjustment based on age is probably not necessary in adults. An analysis of 12 healthy elderly (age 65 and older) patients and young patients (18–40 years) showed essentially no difference in kinetics after single doses of eslicarbazepine acetate 600 mg or at steady state.8 However, there was a faster clearance of eslicarbazepine acetate in younger children compared to older children and adolescents.14 Age-dependent differences may need to be considered in the pediatric population.

Effect of other drugs on eslicarbazepine acetate

Clearance of eslicarbazepine was shown to be increased by concurrent treatment with carbamazepine in a dose-dependent manner and by co-administration of barbiturates and phenytoin. Lamotrigine, valproic acid, topiramate, gabapentin, clobazam, and levetiracetam showed no effect on eslicarbazepine exposure.15 Therefore, when administered with carbamazepine, barbiturates, or phenytoin, serum concentrations of eslicarbazepine may be slightly lower than expected, most likely due to induction of UDT-glucuronosyltransferase enzymes.5 

Effect of eslicarbazepine acetate on other drugs

Eslicarbazepine acetate did not affect the clearance of clobazam, gabapentin, phenytoin, phenobarbital, levetiracetam and valproic acid. Eslicarbazepine acetate slightly increased the clearance of carbamazepine, lamotrigine, and topiramate. However, none of these pharmacokinetic interactions appear clinically significant and dose adjustment is not expected to be necessary in most patients taking concurrent anticonvulsants.15 

In three Phase III clinical trials, all with similar design, patients were assessed for eight weeks for baseline seizures. They were then randomized to placebo, 400 mg, 800 mg, or 1200 mg of eslicarbazepine acetate.9,10,11 One of the three trials did not include a 400 mg group.10 There was a two-week dose titration period followed by 12–14 weeks of maintenance therapy. Titration schedules varied between trials. Inclusion criteria included men or women age ≥ 18 with a diagnosis of simple or complex partial seizures, who had at least four partial-onset seizures in the four weeks prior to screening and during each of the two 4-week baseline assessment periods. In addition, they had to be concurrently treated with one or two anticonvulsants at a standard dose for at least two months prior to the study.

During the maintenance phase, more patients obtained a 50% reduction in the number of seizures in the 800 mg and 1200 mg groups compared to placebo (Table 1). Eslicarbazepine acetate showed a dose-dependent reduction in seizure frequency that was significant in the 800 mg and 1200 mg groups, but was not significant at 400 mg (Table 2). More patients were seizure free in the 800 mg and 1200 mg groups than in the placebo groups, but this finding did not reach significance (Table 3).9,10,11 An open-label continuation of one of the phase III clinical trials showed that benefits continued up to one year, with the mean maintenance dose required being 877 mg per day, showing that 800 mg daily may be the optimal maintenance dose for most patients. The number of patients that were seizure free during each twelve-week interval remained relatively constant during the year.16 

Table 1:

Percentage of Patients with 50% Reduction in Number of Seizures

Percentage of Patients with 50% Reduction in Number of Seizures
Percentage of Patients with 50% Reduction in Number of Seizures
Table 2:

Median Percent Reduction in Seizure Frequency

Median Percent Reduction in Seizure Frequency
Median Percent Reduction in Seizure Frequency
Table 3:

Percentage of Patients who Remained Seizure Free at End of Study

Percentage of Patients who Remained Seizure Free at End of Study
Percentage of Patients who Remained Seizure Free at End of Study

In clinical trials, the incidence of adverse events increased with dose of eslicarbazepine acetate. Overall, over 50% of patients experienced an adverse event, but most were mild to moderate in severity and occurred almost exclusively within the first six weeks of treatment. Discontinuation rates for eslicarbazepine acetate-treated patients were not significantly different than for placebo-treated patients. The most common adverse events (>10% in at least one clinical trial) were dizziness, somnolence, headache, nausea, and diplopia. There was no statistically significant difference in serious adverse events between treatment groups and placebo. A rash occurred in three patients and asymptomatic hyponatremia occurred in one patient who was also taking carbamazepine.9,10,11,12 In the open-label follow up trial, no laboratory abnormalities were deemed clinically relevant after one year of treatment and there were no relevant changes in vital signs, weight, or ECG parameters.16 

Unlike carbamazepine and oxcarbazepine, eslicarbazepine acetate is not metabolized to a 10,11-epoxide, a metabolite that is thought to be responsible for enzyme induction and some serious adverse effects of these agents.4 Eslicarbazepine acetate is metabolized almost exclusively to the active S-isomer,6 while the ratio of the S to R metabolite of oxcarbazepine is approximately 4:1.17 Because the S-isomer is the active form, lower doses of eslicarbazepine acetate may be effective, which could improve its side effect profile. There appears to be no increased incidence of potentially serious adverse events such as rash, hyponatremia, or blood dyscrasias when compared to placebo.9,11,12,16 Also, eslicarbazepine acetate does not require a complicated titration schedule and is dosed once daily where carbamazepine (IR) may require dosing up to four times a day and oxcarbazepine is dosed twice daily.10 

If approved, eslicarbazepine acetate will offer another option for adjunct therapy in patients whose seizures are uncontrolled on their current therapy. It may be a good choice in patients who have had intolerable side effects with carbamazepine or oxcarbazepine, in patients with mild to moderate liver failure, or in patients who would benefit from once-daily dosing to improve adherence.

In their one-year follow up of a clinical trial population, Halasz, et al. also assessed the effect of eslicarbazepine acetate on depressive symptoms as evidenced by change in the Montgomery Asberg Depression Rating Scale (MADRS) from baseline to treatment discontinuation or 1 year. The MADRS is a ten-item assessment measuring depressive symptoms on a scale of 0 to 6. The final score is the total sum of the 10 items with 0 indicating least depressed and 60 indicating most severely depressed. Participants showed a statistically significant decrease from baseline in MADRS score from baseline to the end of the study.16 However, the average baseline MADRS score decreased from 9.5 to 7.2, both indicating mild depression, so the decrease was unlikely to be clinically significant. No other published studies have examined the effectiveness of eslicarbazepine acetate for other mental health indications. Research is needed in bipolar or depressed populations to determine if eslicarbazepine acetate would be effective.

1.
Zebenix (eslicarbazepine acetate)
.
Summary for the public. European Medicines Agency
.
2.
Sunovion Pharmaceuticals Press Release. 12/11/2011. Available from: http://eon.businesswire.com/news/eon/20111202005053/en/STEDESA/esli carbazepine-acetate/Sunovion. Accessed October 19, 2012
.
3.
Benes
J
,
Parada
A
,
Figueiredo
AA
,
Alves
PC
,
Freitas
AP
,
Learmonth
DA
,
et al.
Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives
.
J Med Chem
.
1999
;
42
(
14
):
2582
7
.
DOI: 10.1021/jm980627g. PubMed PMID: 10411478
.
4.
Bonifácio
MJ
,
Sheridan
RD
,
Parada
A
,
Cunha
RA
,
Patmore
L
,
Soares-da-Silva
P.
Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine
.
Epilepsia
.
2001
;
42
(
5
):
600
8
.
PubMed PMID: 11380566
.
5.
Loureiro
AI
,
Fernandes-Lopes
C
,
Bonifácio
MJ
,
Wright
LC
,
Soares-da-Silva
P.
Hepatic UDP-glucuronosyltransferase is responsible for eslicarbazepine glucuronidation
.
Drug Metabolism and Disposition
.
2011
;
39
(
9
):
1486
94
.
DOI: 10.1124/dmd.111.038620. PubMed PMID: 21673130
.
6.
Almeida
L
,
Soares-da-Silva
P.
Eslicarbazepine acetate (BIA 2-093)
.
Neurotherapeutics
.
2007
;
4
(
1
):
88
96
. .
7.
Maia
J
,
Almeida
L
,
Falcão
A
,
Soares
E
,
Mota
F
,
Potgieter
MA
,
et al
.
Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate
.
Int J Clin Pharmacol Ther
.
2008
;
46
(
3
):
119
30
. .
8.
Almeida
L
,
Falcão
A
,
Maia
J
,
Mazur
D
,
Gellert
M
,
Soares-da-Silva
P.
Single-dose and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2-093) in healthy elderly and young subjects
.
J Clin Pharmacol
.
2005
;
45
(
9
):
1062
6
. .
9.
Elger
C
,
Halász
P
,
Maia
J
,
Almeida
L
,
Soares-da-Silva
P.
Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study
.
Epilepsia
.
2009
;
50
(
3
):
454
63
. .
10.
Gil-Nagel
A
,
Lopes-Lima
J
,
Almeida
L
,
Maia
J
,
Soares-da-Silva
P.
Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures
.
Acta Neurol Scand
.
2009
;
120
(
5
):
281
7
. .
11.
Ben-Menachem
E
,
Gabbai
AA
,
Hufnagel
A
,
Maia
J
,
Almeida
L
,
Soares-da-Silva
P.
Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy
.
Epilepsy Res
.
2010
;
89
(
2–3
):
278
85
. .
12.
Elger
C
,
Bialer
M
,
Cramer
JA
,
Maia
J
,
Almeida
L
,
Soares-da-Silva
P.
Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures
.
Epilepsia
.
2007
;
48
(
3
):
497
504
. .
13.
Almeida
L
,
Potgieter
JH
,
Maia
J
,
Potgieter
MA
,
Mota
F
,
Soares-da-Silva
P.
Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment
.
Eur J Clin Pharmacol
.
2008
;
64
(
3
):
267
73
. .
14.
Almeida
L
,
Minciu
I
,
Nunes
T
,
Butoianu
N
,
Falcão
A
,
Magureanu
SA
,
et al
.
Pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate in children and adolescents with epilepsy
.
J Clin Pharmacol
.
2008
;
48
(
8
):
966
77
. .
15.
Falcão
A
,
Fuseau
E
,
Nunes
T
,
Almeida
L
,
Soares-da-Silva
P.
Pharmacokinetics, drug interactions and exposure-response relationship of eslicarbazepine acetate in adult patients with partial-onset seizures: population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses
.
CNS Drugs
.
2012
;
26
(
1
):
79
91
. .
16.
Halasz
P
,
Cramer
JA
,
Hodoba
D
,
Członkowska
A
,
Guekht
A
,
Maia
J
,
et al
.
Long-term efficacy and safety of eslicarbazepine acetate: results of a 1-year open-label extension study in partial-onset seizures in adults with epilepsy
.
Epilepsia
.
2010
;
51
(
10
):
1963
9
. .
17.
Lloyd
P
,
Flesch
G
,
Dieterle
W
.
Clinical pharmacology and pharmacokinetics of oxcarbazepine
.
Epilepsia
.
1994
;
35
(
s3
):
S10
S13
. .